ClinVar Genomic variation as it relates to human health

Observed in the heterozygous state and with a second ABCC8 variant in individuals affected with hyperinsulinism; in one patient, the variant inherited from mother affected with diffuse hyperinsulinism (Mohnike et al., 2014; Dung et al., 2013; Ponzi et al., 2018; Panigrahy et al., 2022; Yorifuji et al., 2023); Observed in a patient diagnosed with diffuse congenital hyperinsulinism in published literature; variant inherited from unaffected father, and authors conclude the variant is likely recessive and the patient likely had misdiagnosed focal hyperinsulinism, rather than diffuse (Saint-Martin et al., 2015); Published functional studies demonstrate a damaging effect on protein trafficking (Saint-Martin et al., 2015); Not observed in large population cohorts (gnomAD); Also known as c.4135G>A p.G1379S; This variant is associated with the following publications: (PMID: 24814349, : 36504295, 30193751, 24401662, 34304300)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1378 of the ABCC8 protein (p.Gly1378Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital hyperinsulinism (CHI) (PMID: 34304300). This variant has been reported in individual(s) with autosomal dominant ABCC8-related conditions (PMID: 24401662, 24814349, 36504295); however, the role of the variant in this condition is currently unclear. This variant is also known as c.4135G>A (p.Gly1379Ser). ClinVar contains an entry for this variant (Variation ID: 1338261). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 24814349). This variant disrupts the p.Gly1378 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16357843, 23275527). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.